Cd22 chimeric antigen receptor (car) therapies

Abstract

The invention provides compositions and methods for treating cancer, e.g., hematological cancer, by administering a CD22 CAR-expressing cell described herein according to a dosage regimen described herein. Also disclosed are methods of making and compositions comprising the same.

What is claimed is: 
     
         1 . A method of treating a young adult or a pediatric subject having a hematological cancer comprising administering to the subject an effective number of cells that express a chimeric antigen receptor (CAR) molecule that binds CD22, e.g., a CD22 CAR, wherein the CD22 CAR-expressing cells are administered according to a dose fractionation dosing regimen, e.g., a split-dosing regimen. 
     
     
         2 . A composition comprising cells that express a chimeric antigen receptor (CAR) molecule that binds CD22, e.g., a CD22 CAR, for use in the treatment of a young adult or a pediatric subject having a hematological cancer comprising administering to the subject an effective number of said cells wherein the CD22 CAR-expressing cells are administered according to a dose fractionation dosing regimen, e.g., a split-dosing regimen. 
     
     
         3 . The method of  claim 1  or the composition for use of  claim 2 , wherein the CD22 CAR-expressing cells are administered:
 a. at a dose of about 0.02×10 7  to 5.0×10 7  viable CD22 CAR-expressing cells/kg, when the subject weighs <50 kg; or 
 b. at a dose of about 0.5×10 8  to 10×10 8  viable CD22 CAR-expressing cells, when the subject weighs ≥50 kg. 
 
     
     
         4 . A method of treating a subject having a hematological cancer, comprising administering to the subject an effective number of cells that express a chimeric antigen receptor (CAR) molecule that binds CD22, e.g., a CD22 CAR, wherein the CD22 CAR-expressing cells are administered:
 a. at a dose of about 0.02×10 7  to 5.0×10 7  viable CD22 CAR-expressing cells/kg, when the subject weighs <50 kg; or   b. at a dose of about 0.5×10 8  to 10×10 8  viable CD22 CAR-expressing cells, when the subject weighs ≥50 kg.   
     
     
         5 . A composition comprising cells that express a chimeric antigen receptor (CAR) molecule that binds CD22, e.g., a CD22 CAR, for use in the treatment of a subject having a hematological cancer comprising administering to the subject an effective number of said cells wherein the CD22 CAR-expressing cells are administered:
 a. at a dose of about 0.02×10 7  to 5.0×10 7  viable CD22 CAR-expressing cells/kg, when the subject weighs <50 kg; or   b. at a dose of about 0.5×10 8  to 10×10 8  viable CD22 CAR-expressing cells, when the subject weighs ≥50 kg.   
     
     
         6 . The method of  claim 4  or the composition for use of  claim 5 , wherein the CD22 CAR-expressing cells are administered according to a dose fractionation dosing regimen, e.g., a split-dosing regimen. 
     
     
         7 . The method or the composition for use of any of the preceding claims, wherein the hematological cancer is B cell ALL, e.g., relapsed and/or refractory B cell ALL. 
     
     
         8 . The method or the composition for use of any of the preceding claims, wherein the subject is a young adult or a pediatric subject, e.g., aged about 1-29 years, e.g., aged 1-29 years. 
     
     
         9 . The method of any of  claim 1 ,  3  or  6 , or the composition for use of any of  claim 2 - 3  or  6 , wherein the dose fractionation dosing regimen comprises a total dose administered in, e.g., one, two, three, or more separate administrations of a partial dose. 
     
     
         10 . The method of any of  claim 1 ,  3 ,  6  or  9 , or the composition for use of any of  claim 2 - 3 ,  6  or  9 , wherein the dose fractionation dosing regimen comprising a total dose comprises three administrations of a partial dose, e.g., a first partial dose, a second partial dose and a third partial dose. 
     
     
         11 . The method or composition for use of  claim 9  or  10 , wherein the first partial dose comprises a first percentage of the total dose and is administered on a first day of treatment. 
     
     
         12 . The method or composition for use of  claim 11 , wherein the first percentage comprising the first partial dose is about 10% (e.g., 10%) of the total dose. 
     
     
         13 . The method or composition for use of  claim 9  or  10 , wherein the second partial dose comprises a second percentage of the total dose and is administered on a second day of treatment. 
     
     
         14 . The method or composition for use of  claim 13 , wherein the second percentage comprising the second partial dose is about 30% (e.g., 30%) of the total dose. 
     
     
         15 . The method or composition for use of  claim 9  or  10 , wherein the third partial dose comprises a third percentage (e.g., the remaining percentage) of the total dose and is administered on a third day of treatment. 
     
     
         16 . The method or composition for use of  claim 15 , wherein the third percentage comprising the third partial dose is about 60% (e.g., 60%) of the total dose. 
     
     
         17 . The method or composition for use of any of  claims 10 - 16 , wherein the first partial dose, the second partial dose and the third partial dose are administered on consecutive days. 
     
     
         18 . The method or composition for use of any of  claim 1 - 2  or  9 - 17 , wherein the total cell dose comprises about 0.02×10 7  to 5.0×10 7  (e.g., about 0.2×10 7  to 1.0×10 7 ) CD22 CAR-expressing cells/kg or about 0.5×10 8  to 10×10 8  (e.g., about 1×10 8  to 5×10 8 ) CD22 CAR-expressing cells. 
     
     
         19 . The method or composition for use of  claim 18 , wherein the total cell dose comprises about 0.2×10 7  to 1.0×10 7  CD22 CAR-expressing cells/kg. 
     
     
         20 . The method or composition for use of  claim 18  or  19 , wherein:
 a. the first partial dose, e.g., 10% of the total dose, comprises about 0.2×10 6  to 1×10 6  CD22 CAR-expressing cells/kg; 
 b. the second partial dose, e.g., 30% of the total dose, comprises about 0.6×10 6  to 3×10 6  CD22 CAR-expressing cells/kg; and 
 c. the third partial dose, e.g., 60% of the total dose, comprises about 1.2×10 6  to 6×10 6  CD22 CAR-expressing cells/kg. 
 
     
     
         21 . The method or composition for use of any of  claims 18 - 20 , wherein the subject weighs less than 50 kg. 
     
     
         22 . The method or composition for use of  claim 18 , wherein the total cell dose comprises about 1×10 8  to 5×10 8  CD22 CAR-expressing cells/kg. 
     
     
         23 . The method or composition for use of  claim 18  or  22 , wherein:
 a. the first partial dose, e.g., 10% of the total dose, comprises about 1×10 7  to 5×10 7  CD22 CAR-expressing cells; 
 b. the second partial dose, e.g., 30% of the total dose, comprises about 0.3×10 7  to 1.5×10 8  CD22 CAR-expressing cells; and 
 c. the third partial dose, e.g., 60% of the total dose, comprises about 0.6×10 8  to 3×10 8  CD22 CAR-expressing cells. 
 
     
     
         24 . The method or composition for use of any of  claim 18  or  22 - 23 , wherein the subject weighs 50 kg or more than 50 kg. 
     
     
         25 . The method of  claim 3  or  4 , or the CD22 CAR-expressing cells for use of  claim 3  or  5 , wherein the CD22 CAR-expressing cells are administered at:
 a. a dose of about 0.02×10 7  to 1×10 7 , about 1×10 7  to 1.5×10 7 , about 1.5×10 7  to 2×10 7 , about 2×10 7  to 2.5×10 7 , about 2.5×10 7  to 3×10 7 , about 3×10 7  to 3.5×10 7 , about 3.5×10 7  to 4×10 7 , about 4×10 7  to 4.5×10 7 , or about 4.5×10 7  to 5×10 7  viable CD22 CAR-expressing cells/kg, when the subject weighs <50 kg; 
 b. a dose of about 0.02×10 7 , about 0.04×10 7 , about 0.06×10 7 , about 0.08×10 7 , about 1×10 7 , about 1.5×10 7 , about 2×10 7 , about 2.5×10 7 , about 3×10 7 , about 3.5×10 7 , about 4×10 7 , about 4.5×10 7 , or about 5×10 7  viable CD22 CAR-expressing cells/kg, when the subject weighs <50 kg; 
 c. a dose of about 0.5×10 8  to 1×10 8 , about 1×10 8  to 1.5×10 8 , about 1.5×10 8  to 2×10 8 , about 2×10 8  to 2.5×10 8 , about 2.5×10 8  to 3×10 8 , about 3×10 8  to 3.5×10 8 , about 3.5×10 8  to 4×10 8 , about 4×10 8  to 4.5×10 8 , about 4.5×10 8  to 5×10 8 , about 5×10 8  to 6×10 8 , about 6×10 8  to 7×10 8 , about 7×10 8  to 8×10 8 , about 8×10 8  to 9×10 8 , or about 9×10 8  to 10×10 8  viable CD22 CAR-expressing cells, when the subject weighs ≥50 kg; or 
 d. a dose of about 0.5×10 8 , about 1×10 8 , about 1.5×10 8 , about 2×10 8 , about 2.5×10 8 , about 3×10 8 , about 3.5×10 8 , about 4×10 8 , about 4.5×10 8 , about 5×10 8 , about 6×10 8 , about 7×10 8 , about 8×10 8 , about 9×10 8 , about 10×10 8  viable CD22 CAR-expressing cells, when the subject weighs ≥50 kg. 
 
     
     
         26 . The method of any of  claim 3 - 4  or  25 , or the CD22 CAR-expressing cells for use of any of  claim 3 ,  5  or  25 , wherein the CAR-expressing cells are administered
 a. at a dose of about 0.2×10 7  to 1×10 7  viable CD22 CAR-expressing cells/kg, when the subject weighs <50 kg; or 
 b. at a dose of about 1×10 8  to 5×10 8  viable CD22 CAR-expressing cells, when the subject weighs ≥50 kg. 
 
     
     
         27 . The method of any of  claim 6 - 14 , or  25 - 26 , or the CD22 CAR-expressing cells for use of any of  claim 6 - 14  or  25 - 26 , wherein when the subject weighs <50 kg, the total dose comprises about 0.2×10 7  to 1×10 7  viable CD22 CAR-expressing cells/kg, and wherein
 a. the first partial dose, e.g., 10% of the total dose, comprises about 0.2×10 6  to 1×10 6  CD22 CAR-expressing cells/kg; 
 b. the second partial dose, e.g., 30% of the total dose, comprises about 0.6×10 6  to 3×10 6  CD22 CAR-expressing cells/kg; and 
 c. the third partial dose, e.g., 60% of the total dose, comprises about 1.2×10 6  to 6×10 6  CD22 CAR-expressing cells/kg. 
 
     
     
         28 . The method of any of  claim 6 - 14 , or  25 - 26 , or the CD22 CAR-expressing cells for use of any of  claim 6 - 14  or  25 - 26 , wherein when the subject weighs ≥50 kg, the total dose comprises about 1×10 8  to 5×10 8  viable CD22 CAR-expressing cells, and wherein
 a. the first partial dose, e.g., 10% of the total dose, comprises about 1×10 7  to 5×10 7  CD22 CAR-expressing cells; 
 b. the second partial dose, e.g., 30% of the total dose, comprises about 0.3×10 7  to 1.5×10 8  CD22 CAR-expressing cells; and 
 c. the third partial dose, e.g., 60% of the total dose, comprises about 0.6×10 8  to 3×10 8  CD22 CAR-expressing cells. 
 
     
     
         29 . The method or composition for use of  claim 9 , comprising administering an additional dose of CD22 CAR-expressing cells. 
     
     
         30 . The method or composition for use of  claim 29 , wherein the additional dose, e.g., supplemental dose, of CD22 CAR-expressing:
 a. comprises about 0.6×10 6  to 3×10 6  cells/kg or about 0.3×10 8  to 1.5×10 8  cells;   b. comprises less than about 1.2×10 6  to 6×10 6  cells/kg or about 0.6×10 8  to 3×10 8  cells; or   c. is administered at least 13 days after administration of the first partial dose of CD22 CAR-expressing cells, e.g., administered on day 14 or later.   
     
     
         31 . The method or composition for use of any of the preceding claims, further comprising administering to the subject an effective number of cells that express a CAR molecule that binds CD19, e.g., a CD19 CAR. 
     
     
         32 . The method or composition for use of  claim 31 , wherein the CD22 CAR-expressing cells are administered before, after or concurrently with the administration of the CD19 CAR-expressing cells. 
     
     
         33 . The method or composition for use of  claim 31  or  32 , wherein the CD19 CAR-expressing cells are administered as a single dose infusion, e.g., a total dose is administered in a single infusion, e.g., at a dose of about 0.2×10 6  to 10×10 6  CD19 CAR-expressing cells/kg, e.g., about 2.0×10 6  CD19 CAR-expressing cells/kg. 
     
     
         34 . The method or composition for use of  claim 31  or  32 , wherein the CD19 CAR-expressing cells are administered according to a dose fractionation dosing regimen, e.g., split-dosing regimen described herein, wherein the dose fractionation dosing regimen comprises a total dose administered in, e.g., one, two, three, or more separate administrations of a partial dose. 
     
     
         35 . The method or compositions for use of  claim 34 , wherein the dose fractionation dosing regimen comprising a total dose comprises three administrations of a partial dose, e.g., a first partial dose, a second partial dose and a third partial dose. 
     
     
         36 . The method or composition for use of  claim 35 , wherein:
 a. the first partial dose comprises a first percentage (e.g., about 10%) of the total dose; and is administered on a first day of treatment;   b. the second partial dose comprises a second percentage (e.g., about 30%) of the total dose; and is administered on a second day of treatment; and   c. the third partial dose comprises a third percentage (e.g., about 60%) of the total dose; and is administered on a third day of treatment.   
     
     
         37 . The method or composition for use of  claim 35  or  36 , wherein the first partial dose, the second partial dose and the third partial dose are administered on consecutive days. 
     
     
         38 . The method or composition for use of any of  claims 35 - 37 , wherein the total cell dose comprises about 0.2×10 6  to 10×10 6  CD19 CAR-expressing cells/kg, e.g., about 2.0×10 6  CD19 CAR-expressing cells/kg. 
     
     
         39 . The method or composition for use of any of  claims 35 - 38 , wherein the first partial dose comprises about 0.2×10 6  CD19 CAR-expressing cells/kg, the second partial dose comprises about 0.6×10 6  CD19 CAR-expressing cells/kg, and the third partial dose comprises about 1.2×10 6  CD19 CAR-expressing cells/kg. 
     
     
         40 . The method or composition for use of any of the preceding claims, wherein the subject has been administered lymphodepleting chemotherapy. 
     
     
         41 . The method or composition for use of any of the preceding claims, wherein the subject has not been administered lymphodepleting chemotherapy. 
     
     
         42 . The method or composition for use of any of  claims 31 - 41 , wherein the subject has not relapsed to treatment with cells that express a CAR molecule, e.g., a CD19 CAR or a CD22 CAR therapy (e.g., a CD19 CAR monotherapy or a CD22 CAR monotherapy). 
     
     
         43 . The method or composition for use of any of  claims 31 - 42 , administration of the combination comprising a CD19 CAR and CD22 CAR prevents relapse in the subject, relative to a CD19 CAR monotherapy or a CD22 CAR monotherapy, or relative to a subject that has not received the combination. 
     
     
         44 . The method or composition for use of any of the preceding claims, wherein the cancer, e.g., a sample from the subject containing cancer cells, comprises cells that express CD19 and/or CD22. 
     
     
         45 . The method or composition for use of any of the preceding claims, wherein the CD22 CAR molecule comprises a CD22 binding domain, a transmembrane domain, and an intracellular signaling domain, and wherein said CD22 binding domain comprises one or more of light chain complementarity determining region 1 (LC CDR1), light chain complementarity determining region 2 (LC CDR2), and light chain complementarity determining region 3 (LC CDR3) of any CD22 light chain binding domain amino acid sequence listed in Table 6, 8 or 10, and one or more of heavy chain complementarity determining region 1 (HC CDR1), heavy chain complementarity determining region 2 (HC CDR2), and heavy chain complementarity determining region 3 (HC CDR3) of any CD22 heavy chain binding domain amino acid sequence listed in Table 6, 7, or 9. 
     
     
         46 . The method or composition for use of any of the preceding claims, wherein the CD22 CAR molecule comprises the amino acid sequence of SEQ ID NO: 835, or an amino acid sequence with at least 95% identity thereto. 
     
     
         47 . The method or composition for use of any of the preceding claims, wherein the CD22 CAR molecule comprises a CD22 binding domain comprising a light chain variable region of SEQ ID NO: 1333, or an amino acid sequence with at least 95% identity thereto, and a heavy chain variable region of SEQ ID NO: 1332, or an amino acid sequence with at least 95% identity thereto. 
     
     
         48 . The method or composition for use of any of  claims 31 - 43 , wherein the CD19 CAR molecule comprises a CD19 binding domain, a transmembrane domain, and an intracellular signaling domain, and wherein said CD19 binding domain comprises one or more of (e.g., all three of) light chain complementarity determining region 1 (LC CDR1), light chain complementarity determining region 2 (LC CDR2), and light chain complementarity determining region 3 (LC CDR3) of any CD19 scFv or light chain binding domain amino acid sequence listed in Tables 2 or 3, and one or more of (e.g., all three of) heavy chain complementarity determining region 1 (HC CDR1), heavy chain complementarity determining region 2 (HC CDR2), and heavy chain complementarity determining region 3 (HC CDR3) of any CD19 scFv or heavy chain binding domain amino acid sequence listed in Tables 2 or 3. 
     
     
         49 . The method or composition for use of any of  claim 31 - 43  or  47 , wherein the CD19 CAR molecule comprises any light chain variable region of a scFv listed in Tables 2 or 3 and any heavy chain variable region of a scFv listed Tables 2 or 3. 
     
     
         50 . The method or composition for use of  claim 48 , wherein the CD19 CAR molecule comprises a CD19 binding domain comprising the amino acid sequence of SEQ ID NO:2, or SEQ ID NO: 59, or an amino acid sequence with at least 95% identity thereto. 
     
     
         51 . The method or composition for use of any of the preceding claims, wherein the CAR molecule comprises a transmembrane domain of a protein selected from the group consisting of the alpha, beta or zeta chain of the T-cell receptor, CD28, CD3 epsilon, CD45, CD4, CD5, CD8, CD9, CD16, CD22, CD33, CD37, CD64, CD80, CD86, CD134, CD137 and CD154. 
     
     
         52 . The method or composition for use of any of  claims 45 - 51 , wherein the antigen binding domain is connected to the transmembrane domain by a hinge region. 
     
     
         53 . The method or composition for use of any of  claims 45 - 52 , wherein the hinge region comprises SEQ ID NO:14, or an amino acid sequence with at least 95% identity thereto. 
     
     
         54 . The method or composition for use of any of  claims 45 - 53 , wherein the intracellular signaling domain:
 a. comprises a costimulatory domain and/or a primary signaling domain;   b. comprises a costimulatory domain comprising a functional signaling domain obtained from a protein selected from the group consisting of OX40, CD2, CD27, CD28, CDS, ICAM-1, LFA-1 (CD11a/CD18), ICOS (CD278), and 4-1BB (CD137),   c. comprises a costimulatory domain comprising the amino acid sequence of SEQ ID NO:16 or SEQ ID NO:51;   d. comprises a functional signaling domain of 4-1BB and/or a functional signaling domain of CD3 zeta; or   e. comprises the amino acid sequence of SEQ ID NO: 16 and/or the amino acid sequence of SEQ ID NO:17 or SEQ ID NO:43.   
     
     
         55 . The method or composition for use of any of  claims 45 - 54 , wherein the CAR molecule further comprises a leader sequence, wherein, optionally, the leader sequence comprises SEQ ID NO: 13. 
     
     
         56 . The method or composition for use of any of the preceding claims, wherein the CAR-expressing cells comprise T cells (e.g., CD8+ or CD4+ T cells) or NK cells. 
     
     
         57 . The method or composition for use of any of the preceding claims, further comprising administering an additional agent, e.g., a checkpoint inhibitor, e.g., as described herein. 
     
     
         58 . The method or composition for use of any of  claim 1 - 6  or  7 - 57 , wherein the hematological cancer:
 a. is associated with expression of CD22 or CD19; 
 b. is a leukemia or lymphoma; 
 c. is a relapsed and/or refractory cancer; or 
 d. is chosen from B-cell acute Lymphoid Leukemia (BALL), T-cell acute Lymphoid Leukemia (TALL), acute lymphoid leukemia (ALL), Prolymphocytic leukemia, Chronic myeloid leukemia (CML), blastic plasmacytoid dendritic cell neoplasm, Burkitt's lymphoma, diffuse large B cell lymphoma, Follicular lymphoma, Hairy cell leukemia, small cell- or a large cell-follicular lymphoma, malignant lymphoproliferative conditions, MALT lymphoma, mantle cell lymphoma (MCL), Marginal zone lymphoma, multiple myeloma, acute myeloid leukemia (AML), myelodysplasia and myelodysplastic syndrome, non-Hodgkin lymphoma, Hodgkin lymphoma, or plasmablastic lymphoma. 
 
     
     
         59 . The method or composition for use of any of the preceding claims, wherein the subject:
 a. has previously received stem cell transplantation (SCT) therapy, e.g., allogeneic or autologous SCT; or   b. is not eligible for SCT therapy, e.g., allogeneic or autologous SCT.   
     
     
         60 . The method or composition for use of  claim 59 , wherein the subject has previously received SCT therapy and the subject has, or is identified as having relapsed from the SCT therapy. 
     
     
         61 . The method or composition for use of  claim 60 , wherein the relapse from SCT therapy comprises a blood or bone marrow relapse and/or the relapse occurs at least 1-12 months, e.g., at least 6 months, after SCT therapy. 
     
     
         62 . The method or composition for use of any of the preceding claims, wherein the subject has, or is identified as having, a relapse, e.g., a second or greater relapse, e.g., bone marrow relapse, e.g., as described herein. 
     
     
         63 . The method or composition for use of any of the preceding claims, wherein the subject has, or is identified as having relapsed from a CAR-expressing cell therapy, e.g., a CAR-expressing cell therapy other than a CAR22-expressing cell therapy or a CAR19-expressing cell therapy. 
     
     
         64 . The method or composition for use of any of the preceding claims, wherein the subject has, or is identified as not having a response, e.g., a complete response or partial response, in response to one or more (e.g., 2, 3, 4, 5, 6, 7, or 8) chemotherapeutic agents, e.g., as described herein.